The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression
The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression
复制标题
DOI：
10.1172/jci200215887
复制
发表时间：
2002-12-01
影响因子：
15.9
通讯作者：
López-Cabrera, M
中科院分区：
文献类型：
--
作者：
Lara-Pezzi, E;Gómez-Gaviro, MV;López-Cabrera, M
肝细胞癌与慢性B型肝炎病毒（HBV）感染密切相关，且由于肝内转移而预后不良。HBx通常是在肝肿瘤细胞中检测到的唯一HBV蛋白;然而，其对肿瘤侵袭和转移的贡献迄今尚未确定。在这项工作中，我们表明，HBx增强肿瘤细胞的侵袭，在体内和体外。由HBx诱导的侵袭能力增加是通过上调膜I型基质金属蛋白酶（MT 1-MMP）表达介导的，其反过来激活基质金属蛋白酶-2。HBx对MT 1-MMP表达和细胞侵袭的诱导依赖于环氧化酶-2（考克斯-2）活性。此外，HBx上调考克斯-2的表达，这是由考克斯-2基因启动子的转录激活以活化的T细胞依赖性（NF-AT依赖性）的核因子方式介导的。这些结果表明HBx通过涉及MT 1-MMP和考克斯-2的上调的机制促进肿瘤细胞侵袭的能力，并提供了对这种病毒蛋白的作用机制及其参与肝细胞癌的肿瘤转移和复发的新见解。
Hepatocellular carcinoma is strongly associated with chronic infection by the hepatitis B virus (HBV) and has poor prognosis due to intrahepatic metastasis. HBx is often the only HBV protein detected in hepatic tumor cells; however, its contribution to tumor invasion and metastasis has not been established so far. In this work, we show that HBx enhances tumor cell invasion, both in vivo and in vitro. The increased invasive capacity induced by HBx is mediated by an upregulation of membrane-type I matrix metalloproteinase (MT1-MMP) expression, which in rum activates matrix metalloproteinase-2. Induction of both MT1-MMP expression and cell invasion by HBx is dependent on cyclooxygenase-2 (COX-2) activity. In addition, HBx upregulates the expression of COX-2, which is mediated by the transcriptional activation of the COX-2 gene promoter in a nuclear factor of activated T cell-dependent (NF-AT-dependent) manner. These results demonstrate the ability of HBx to promote tumor cell invasion by a mechanism involving the upregulation of MT1-MMP and COX-2 and provide new insights into the mechanism of action of this viral protein and its involvement in tumor metastasis and recurrence of hepatocellular carcinoma.